Periodontal disease is caused by bacterial pathogens that thrive in a complex microbial community, which forms in the gingival pocket. The initiation and growth of this bacterial biofilm likely requires sophisticated molecular communication among the bacterial various species in this community. A chemical signal produced by the LuxS gene has recently been suggested to represent a broadly distributed mechanism for interspecies communication. We have shown that LuxS is present in periodontal pathogens (A. actinomycetemomitans and P. gingivalis) and that the LuxS-dependent signal directs specific interspecies responses in these organisms. In this application, we will determine the range and specificity of LuxS-dependent communication among various oral and non-oral organisms, the mechanism by which this signaling pathway modulates iron acquisition by Aa and Pg and the role that signaling plays in the virulence of these organisms. We will complement LuxS-deficient strains of Aa and Pg with signals and/or/luxS genes from other oral and non-oral organisms. We will also determine if Aa or Pg respond differently to cognate and heterologous signals. Next, we will examine the growth of signal deficient strains in various iron sources and determine the role that LuxS dependent signaling plays in controlling genes involved in the uptake of iron by Pg and Aa. We have also shown that signaling regulates the expression of virulence-associated genes, thus the contribution of signaling to virulence will be determined in vivo using a mouse model. Finally, we will determine how signal information is transmitted within the bacterial cell to generate a specific response. Potential candidate proteins that may function in signal transduction have been identified; their genes will be inactivated and the resulting bacterial strains will be tested for their response to signal. These studies will provide some of the first evidence showing that LuxS-dependent signaling mediates intra- and interspecies communication among periodontal pathogens. This in turn may lead to the development of new therapeutics that may control growth and development of complex bacterial communities by blocking their communication pathways.